Selective 1,5-alkylidenecarbene insertion reactions on [3.2.1] oxabicyclic ethers: A new approach toward the AB ring system of ingenol

Organic Letters

Volumn 6, Issue 17, 2004, Pages 2961-2964

  Grainger, Richard S ^a   Owoare, Richard B ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

1,5 ALKYLIDENECARBENE; ACETONE; CARBENOID; CARBON; ETHER DERIVATIVE; HYDROGEN; INGENOL; KETONE DERIVATIVE; OXYGEN; SILICON; TRIMETHYLSILYL DERIVATIVE; UNCLASSIFIED DRUG; VINYL CHLORIDE;

ALDOL REACTION; ARTICLE; CHEMICAL BOND; CHEMICAL STRUCTURE; SYNTHESIS; TECHNIQUE; WITTIG REACTION;

CATALYSIS; DITERPENES; ETHERS, CYCLIC; MODELS, MOLECULAR; MOLECULAR STRUCTURE; STEREOISOMERISM;

EID: 4444308035     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol048911r     Document Type: Article

References (48)

1. For a review of early work, see: Kirmse, W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1164.
2. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
3. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
4. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
5. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
6. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
7. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
8. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
9. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
10. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
11. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
12. For recent representative examples of 1,5 C-H insertion reactions of alkylidenecarbenes, see: (a) Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakaedani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004, 45, 1639. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c) Feldman, K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096. (d) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (e) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org. Chem. 2002, 67, 7613. (g) Walker, L. F.; Bourghida, A.; Connolly, S.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965. (h) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011. (i) Ohira, S.; Kuboki, A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 4641. (j) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. For other methods for C-H bond activation, see: (k) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900 and references therein.
13. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
14. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
15. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
16. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
17. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
18. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
19. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
20. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
21. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
22. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
23. Total syntheses of ingenol: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. For a review of approaches to the synthesis of ingenol, see: (c) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. For more recent work, see: (d) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. (e) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265. (f) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296. (g) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927. (h) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Mislin, G. L.; Miesch M. J. Org. Chem. 2003, 68, 433. (k) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J. Org. Chem. 2003, 68, 7899.
24. Relative rates of insertion methine > methylene > methyl can be influenced by the presence of adjacent heteroatoms and by the method used to generate the alkylidenecarbene. See, for example: Taber, D. F.; Christos, T. E. Tetrahedron Lett. 1997, 38, 4927.
25. (a) Gilbert, J. C.; Giamalva, D. H.; Weerasooriya, U. J. Org. Chem. 1983, 48, 5251.
26. (b) Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J. Org. Chem. 1985, 50, 2557.
27. A highly functionalised cis-fused analogue of ingenol has been shown to be devoid of biological activity: Paquette, L. A.; Ross, R.; Springer, J. J. Am. Chem. Soc. 1988, 110, 6192.
28. (a) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 461.
29. (b) Kim, S.; Cho, C. M. Tetrahedron Lett. 1995, 36, 4845.
30. (c) Feldman, K. S.; Wrobleski, M. L. J. Org. Chem. 2000, 65, 8659.
31. (d) Hobley, G. H.; Stuttle, K.; Wills, M. Tetrahedron 2003, 59, 4739.
32. (e) Gais, H.-J.; Reddy, L. R.; Babu, G. S.; Raabe, G. J. Am. Chem. Soc. 2004, 126, 4859. See also ref 2c.
33. (a) Mann, J. Tetrahedron 1986, 42, 4611.
34. (b) Chiu, P.; Lautens, M. In Topics in Current Chemistry; Metz, P., Ed.; Springer-Verlag: New York, 1997; Vol. 190, pp 1-85.
35. (c) Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2004, 43, 1934.
36. Lautens, M.; Bouchain, G. Org. Synth. 2002, 79, 251.
37. List, B.; Shabat, D.; Zhong, G.; Turner, J. M.; Li, A.; Bui, T.; Anderson, J.; Lerner, R. A.; Basbas, C. F., III. J. Am. Chem. Soc. 1999, 121, 7283.
38. While this manuscript was being prepared, Chiu reported the high-yielding addition of the dianion of ethylacetoacetate to oxabicyclic ketone 5: Chiu, P.; Zhang, X.; Ko, R. Y. Y. Tetrahedron Lett. 2004, 45, 1531.
39. Attempted decarboxylation prior to protection results in reformation of ketone 5.
40. Taber, D. F.; Christos, T. E.; Neubert, T. D.; Batra, D. J. Org. Chem. 1999, 64, 9673.
41. 2 on the less hindered exo-face of the internal alkene, followed by intramolecular capture of the bromonium ion intermediate by the axial alcohol.
42. Hopf, H.; Böhm, I.; Kleinschroth, J. Org. Synth. 1981, 60, 41-48.
43. Jacobi, P. A.; Herradura, P. Tetrahedron Lett. 1997, 38, 6621.
44. Paquette, L. A.; Nitz, T. J.; Ross, R. J.; Springer, J. P. J. Am. Chem. Soc. 1984, 106, 1446.
45. Geometrical chloroalkenes are separable in the case of 21. We have observed that (E)-21 cyclizes faster than (Z)-21 under identical reaction conditions.
46. An exception is seen in the work of Wills, whereby 1,5 C-H insertion into the activated methylene of a benzylic ether is preferred over 1,5 O-TBS insertion. However, a MOM methylene CH is less likely to undergo insertion than an O-TBS. See ref 7d.
47. Sueda T.; Nagaoka, T.; Goto, S.; Ochiai, M. J. Am. Chem. Soc. 1996, 118, 10141.
48. 3-C-O-Si dihedral angle 51.1° for chair and 52.2° for boat). Rotation about this carbon-oxygen bond in the chair form shows a conformation where the lone pair and methyl group are synperiplanar to be 6.1-6.5 kcal/mol higher in energy than the lowest energy gauche conformation. Similarly, in the boat form, the synperiplanar orientation of methyl and the oxygen lone pair is 5.5 kcal/mol higher in energy than the gauche conformation. (Equation Presented)